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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [RNA-seq I]

ABSTRACT: In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. Flow cytometric analysis indicated that EGR2 deficient CD8+ T cells had a block in differentiation and failed to undergo terminal exhaustion. To confirm this at a whole transcriptome level, we conducted RNAseq analysis on sorted splenic virus-specific tetramer+ CD8+ T cells isolated at day 20 post-infection with chronic LCMV-Cl13 from either littermate control or EGR2 T cell conditional knock-out mice. The resulting data demonstrated that there was a global loss of the terminally exhausted gene signature within EGR2 KO CD8+ T cells. This suggests that EGR2 promotes terminal CD8+ T cell exhaustion.

ORGANISM(S): Mus musculus

PROVIDER: GSE134689 | GEO | 2021/03/02

REPOSITORIES: GEO

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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [scRNAseq]

Project description:In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. We conducted scRNAseq analysis on sorted virus-specific tetramer+ CD8+ T cells isolated at day 20 post-infection with chronic LCMV-Cl13 from either littermate control or EGR2 T cell conditional knock-out mice. Cells were labelled with hashtags and mixed prior to multiplexed analysis. The resulting data demonstrated that the exhausted cell subsets within EGR2 KO CD8+ T cells have an effector-like phenotype, suggesting that EGR2 stabilises the exhausted state.

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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [ATACseq]

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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [CHIP-seq]

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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [RNA-seq II]

Project description:In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. Flow cytometric analysis indicated that EGR2 is expressed selectively within the progenitor exhausted subset, however a subpopulation of progenitor exhausted cells did not express in EGR2. To define the differences between the EGR2+ and EGR2- progenitor exhausted cells, GFP+ and GFP- polyclonal progenitor exhausted (ie. CD44int-hiPD-1+Slamf6+Tim3-) CD8+ T cells were sorted from Egr2-GFP reporter mice at day 20 p.i. with chronic LCMV-Cl13, and analysed by RNAseq. The resulting data demonstrated that GFP- progenitor cells have a more differentiated phenotype.

2021-03-02 | GSE152849 | GEO

CD39 expression identifies terminally exhausted CD8+ T cells

Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).

2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress

CD39 expression identifies terminally exhausted CD8+ T cells

2015-09-08 | GSE72752 | GEO

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Project description:Altered CD8 T cell differentiation and functional exhaustion prevent control of chronic virus infection and cancer. Yet, how fate commitment and exhaustion are determined and dynamically modulated throughout persistent infection are unclear. We compared the activation and differentiation of LCMV GP33-specific CD8 TCR transgenic cells (P14) primed at the onset versus in the midst of established persistent LCMV-Clone 13 viral infection. LCMV GP33-specific CD8 TCR transgenic (P14) cells were injected into naïve mice immediately infected with LCMV-Cl13 (Early priming) or into mice that had been infected 21 days earlier with LCMV-Cl13 (Late Priming). Sixty hours post-priming P14 cells were sorted from mice and subjected to RNA seq. We show early primed cells very rapidly exhibit a transcriptional profile of robust activation, effector differentiation and dysfunction, while late primed cells have increased expression of genes involved in memory differentiation and maintenance.

2018-10-09 | GSE105044 | GEO

Hypoxia-inducible factors enhance CD8+ T cell effector responses to persistent antigen.

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2013-09-29 | E-GEOD-50158 | biostudies-arrayexpress

EGR2 is Critical for Peripheral Naïve T Cell Differentiation and the T-cell Response to Influenza

Project description:EGR2 is an early growth response transcription factor that negatively regulates T-cell activation, in contrast to its positive regulation by EGR1. Here, we unexpectedly found that EGR2 promotes peripheral naïve T cell differentiation, with delayed TCR-induced proliferation in naïve T cells from Egr2 conditional knockout (CKO) mice, and decreased production of IFN-γ, IL-4, IL-9, and IL-17A in cells subjected to T helper differentiation. Moreover, genes that promote T-cell activation, including Tbx21 and Notch1, had decreased expression in Egr2 CKO T cells and are direct EGR2 target genes. Following influenza infection, Egr2 CKO mice had delayed viral clearance, more weight loss, and more severe pathological changes in the lung than did WT and Egr1 KO mice, with decreased production of effector cytokines and infiltration of antigen-specific memory-precursor CD8+ T cells but lower numbers of lung-resident memory CD8+ T cells. Thus unexpectedly EGR2 can function as a positive regulator that is essential for naïve T-cell differentiation and in vivo T-cell responses to a viral infection.

2014-10-21 | GSE49366 | GEO

RNA-seq analysis of CD8 tumour infiltrating lymphocytes from GFP-Egr2 Knockin and hCD2-Cre Egr2loxP/loxP Egr3-/- mice

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